Impact of chronic infection in the aged on the response to vaccination

描述（由申请人提供）：免疫系统的功能随着年龄的增长而发生深刻的变化。临床上最重要的变化之一是，疫苗在老年人中的效力显著下降，使他们更容易感染流感和肺炎等传染病。这种下降导致总体抗体（Ab）滴度降低以及Ab功能降低。此外，老龄化个体的炎症和慢性炎性感染的发病率增加，这两者都可能对原发性免疫应答的结果产生重大影响。我们目前不知道老年人炎症和感染发生率的增加是否导致他们对感染和疫苗接种的反应能力降低。在这方面，我们已经生成了两组数据，促使我们在此R21应用程序中继续研究此问题。使用具有T细胞受体转基因（TCR Tg）CD 4 T细胞的新型过继转移模型，我们已经表明，与年轻的CD 4 T细胞相比，来自老年个体的幼稚CD 4 T细胞表现出降低的促进对疫苗接种的Ab应答的能力。此外，在初步数据中，我们表明，老年宿主表达的细胞能够产生炎性细胞因子IL-17的频率增加，并且这种频率进一步增加分枝杆菌感染的存在。这些观察结果促使我们提出这样的假设，即CD 4 T细胞的启动和同源功能受到慢性感染的影响，并且T细胞和宿主的年龄加剧了这种影响。为了验证这一假设，我们概述了4个目标，这些目标将确定感染和炎症对CD 4 T细胞对疫苗接种反应的影响。目标1。老年宿主的慢性感染在多大程度上影响年轻幼稚CD 4 T细胞的启动？目标2.慢性感染在多大程度上影响老化的CD 4 T细胞的启动？目标3。慢性感染在多大程度上影响了老年CD 4 T细胞的同源辅助功能？目标4。慢性感染在多大程度上影响CD 4 T细胞记忆的发育和表达？我们将使用TCR Tg T细胞来提供足够数量的均匀幼稚T细胞和低毒力但炎性的分枝杆菌感染（BCG），以在年轻和老年宿主中提供可再现的炎症水平增加。我们可以跟踪T和B细胞对疫苗接种的反应，从而确定感染调节两组细胞反应的程度。这些实验与人类健康有关，因为确定炎症对疫苗接种反应的影响将使我们能够改善老年人的疫苗接种。

DESCRIPTION (provided by applicant): The function of the immune system changes profoundly with age. One of the most clinically important changes is that vaccine efficacy significantly declines in the elderly, leaving them more susceptible to infectious diseases such as influenza and pneumonia. This decline leads to lower overall antibody (Ab) titers as well as reduced Ab function. In addition, aging individuals have an increased incidence of inflammation and chronic inflammatory infections, both of which can potentially have a significant impact on the outcome of a primary immune response. We currently do not know whether the increased incidence of inflammation and infection in the elderly contributes to their reduced ability to respond to infection and vaccination. In this regard we have generated two sets of data that have prompted us to pursue this issue in this R21 application. Using a novel adoptive transfer model with T cell receptor transgenic (TCR Tg) CD4 T cells, we have shown that naive CD4 T cells from aged individuals exhibit a reduced ability to promote Ab responses to vaccination compared to young CD4 T cells. In addition, in the preliminary data, we show that aged hosts express an increased frequency of cells capable of producing the inflammatory cytokine IL-17, and that this frequency is further increased by the presence of mycobacterial infection. These observations prompted us to propose the hypothesis that the priming and cognate function of CD4 T cells is influenced by chronic infection and that age of both T cells and host exacerbate this influence. To test this hypothesis, we have outlined 4 aims that will determine the impact of infection and inflammation on the CD4 T cell response to vaccination. Aim 1. To what extent does chronic infection in the aged host influence the priming of young naive CD4 T cells? Aim 2. To what extent does chronic infection influence the priming of aged CD4 T cells? Aim 3. To what extent does chronic infection influence the cognate helper function of aged CD4 T cells? Aim 4. To what extent does chronic infection influence the development and expression of CD4 T cell memory? We will use TCR Tg T cells to provide sufficient numbers of uniform naive T cells and a low-virulence yet inflammatory mycobacterial infection (BCG) to provide a reproducible increase in the level of inflammation in both young and aged hosts. We can follow both T and B cell responses to vaccination allowing us to determine the extent to which infection modulates the response of both sets of cells. These experiments are relevant to human health since determining the effect of inflammation on the response to vaccination will allow us to improve vaccination in the elderly.